News Release

Expanding Database Enables Discoveries in Emerging Field of Metabolomics

LA JOLLA, CA – September 10, 2012 – Over the last decade, metabolomics
has emerged as the newest of the “omic” sciences (following genomics and
proteomics) to provide comprehensive biochemical information about cellular
metabolism. This new field has revealed that many of the chemicals involved in
or produced through metabolism are currently unknown, but may play vital and
previously unappreciated roles in human health and disease.

A major hurdle in profiling both unknown and known metabolic
compounds (“metabolites”) has been the scarce amount of reference data. But a
team from The Scripps Research Institute has developed a massive, searchable online
metabolite database that is transforming the field and being widely used in
research on countless conditions including cancer and chronic pain.

The researchers describe the newly expanded database, called
METLIN, and its potential benefits in the September issue of the journal Nature Biotechnology.

Getting Off the
Beaten Path

Scientists once focused on only the major metabolic
highways, well-known pathways such as glycolysis and the Krebs Cycle. New
metabolomic studies have shown that other pathways and metabolites, however, also
play critical roles in fundamental biological processes and the progression of
disease.

“For decades biochemical studies have targeted only a
handful of canonical metabolites, and comprehensive profiling has been mostly limited
to genes and proteins,” said Gary Patti, a former postdoctoral fellow at
Scripps Research now an assistant professor at Washington University in St.
Louis who helped develop the database. But now he says the new field of
metabolomics has emerged with huge promise for medical and other advancements.
“I think it’s a really exciting time because the insights being provided by
metabolomics are in some cases affecting the way in which we think about
fundamental biochemistry,” he said.

The sheer number and complexity of metabolites offer
scientists a colossal challenge. While DNA studies of genes that code for
proteins offer clues about how many proteins there are and their functions, there’s
no such map for metabolites—which include a huge range of chemical types, from amino
acids, carbohydrates, and steroids to large, complex fatty acids. No one knows
how many metabolites there are in humans, though the number may well be over
100,000, and other organisms may have their own unique arrays.

Digging In

Metabolites can be isolated and analyzed from almost any
biological specimen, including tissues, blood, urine, and tumors. The most
sensitive technique for analyzing metabolites is mass spectrometry. By using cutting-edge
mass spectrometric technologies, the molecular weight of thousands of
metabolites can be measured within a few minutes. Previously, researchers might
spend days combing databases and other sources of information to identify just
one metabolite of interest.

“If you don’t have a database like METLIN, the value of
metabomic data would be very limited because each study would require manual
searches and ultimately fail to culminate in enough reference data to arrive at
conclusive metabolite identifications,” said team leader Gary Siuzdak, a
metabolomics expert at Scripps Research.

It was against this landscape that Siuzdak’s group
recognized the need for a consolidated and expanded metabolite database to meet
the group’s own needs as it struggled to understand key metabolic processes. Efforts
to build such a resource began in 2004 and the database they dubbed METLIN was initially
built upon slowly. Information was scarce and entered manually, sometimes after
curating chemistry books manually for new structural information. Researchers
in the lab would compete to see who could add the most in a week. Simultaneously,
the lab also began cataloging experimental tandem mass spectrometry data on
these compounds and established the first of such resources to provide
structural information on metabolites that can be used to identify metabolites.

Over the past few years, determined to accelerate their work,
group members gained major momentum largely by partnering with companies like
Sigma, Cayman, ChromaDex, as well as labs at Scripps Research (Boger), University
of California, San Diego (Gerwick), the Joint BioEnergy Institute (Berkeley),
and now Washington University (Patti) to facilitate acquisition of more molecules
on which to generate tandem mass spectrometry data.

More than 10,000 Metabolites

Now METLIN includes more than 60,000 compounds with
detailed, high-resolution tandem mass spectrometry information on more than
10,000 metabolites, by far the largest in the world. And the Siuzdak group is far
from done. “METLIN is still growing as we speak,” said Ralf Tautenhahn, a senior
research associate in Siuzdak’s lab and first author of the paper. “It’s a key
tool for all our projects.” Once a metabolite is identified, researchers can
begin working out how it functions in the body and in disease.

A key benefit of the database is that it goes beyond basic
molecular weight—which might be the same for a range of different compounds. The
tandem mass spectrometry data allows for a higher level of confidence in
identifying these molecules from biological systems. This involves bombarding
individual compounds with gas molecules, which causes them to break apart in
unique ways. The weights of the resulting molecular fragments offer a sort of
chemical signature for each metabolite that researchers can use to match
unknowns more precisely.

Though you can search METLIN manually, the Scripps Research
team has also developed software called XCMS Online that performs detailed
automated searches. Users can input their own data and the coupled XCMS-METLIN system will come back with precise matches, or
if there’s no direct match, it will identify structurally similar metabolites.
“It really does accelerate the whole process of discovering new molecules
associated with diseases and research in many different areas,” said Siuzdak.

Tapping the Potential

The Siuzdak team has already had major successes using the
database. The researchers recently identified a metabolite that is associated
with chronic pain when found in higher than normal levels. Finding ways to
break down this metabolite or to prevent it from forming might lead to new
treatment options for chronic pain sufferers.

Other projects are focused on cancer. While some researchers
are looking for metabolites that might be present in the bloodstream as early
indicators of cancer, Siuzdak’s group is identifying metabolites involved in
cancer’s progression that might offer targets for new therapies. Patti’s lab at
Washington University is further investigating the role of metabolism in
chronic pain and is also looking into metabolite roles in aging and drug
addiction.

But public access means METLIN’s reach stretches far beyond
Scripps Research. “When we first started doing this, I was expecting a couple
of hundred people in the world to use it,” said Siuzdak. Instead, he and his
colleagues were shocked to find users by the thousands exploring a huge range
of topics. Some researchers are looking for metabolites produced after
ingestion of drugs to aid in forensics work; others are interested in ways to
detect signs of pesticide ingestion.

“What’s really exciting about this is seeing that something
we created is being so widely used,” said Siuzdak, “It definitely makes us feel
good to think that we’ve accelerated the progress of science and allowed a lot
of other scientists to do things they wouldn’t have been able to do otherwise.”

This research was funded by the California Institute of
Regenerative Medicine (TR1-01219), the US National Institutes of Health (R24
EY017540, P30 MH062261, RC1 HL101034, P01 DA026146, L30 AG0 038036), and the US
Department of Energy (FG02-07ER64325 and DE-AC0205CH11231).

In addition to Siuzdak, Patti, and Tautenhahn, the other
authors on the paper, “An accelerated workflow for untargeted metabolomics
using the METLIN database,” were Kevin Cho, Winnie Uritboonthai, and Zhengjiang
Zhu, all from The Scripps Research Institute.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.